Donor Lymphocyte Infusion

Number: 0638

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses donor lymphocyte infusion.

1. Medical Necessity

   Aetna considers donor lymphocyte infusion (DLI) medically necessary for persons who have a prior, medically necessary allogeneic bone marrow or peripheral stem cell transplantation. 

2. Experimental and Investigational

   Aetna considers the following procedures experimental and investigational because the effectiveness of these approaches has not been established:

   1. Donor lymphocyte infusion for the treatment of multiple myeloma;
   2. Granulocyte colony-stimulating factor (GCSF)-stimulated donor lymphocyte infusions for improvement of outcomes for relapsed disease following allogeneic hematopoietic cell transplantation;
   3. Intrathecal donor lymphocyte infusion;
   4. Modification of donor lymphocytes (e.g., donor lymphocyte depletion, ex-vivo expansion, expanding antigen-specific T-cell lines, T-cell depletion, chimeric antigen receptor modification, genetic modification);
   5. Pre-transplant infusion of donor lymphocytes treated with extracorporeal photochemotherapy for the prevention of graft rejection following solid organ transplantation;
   6. Use of donor lymphocyte-derived natural killer cells for the treatment of melanoma.

3. Policy Limitations and Exclusions 

   This policy does not apply to FDA-approved chimeric antigen receptor therapy (CAR T), which involves modification of autologous lymphocytes. See CPB 0920 - Tisagenlecleucel (Kymriah) and CPB 0924 - Axicabtagene Ciloleucel (Yescarta).  

4. Related Policies

   • CPB 0641 - Adoptive Immunotherapy and Cellular Therapy
   • CPB 0920 - Tisagenlecleucel (Kymriah)
   • CPB 0924 - Axicabtagene Ciloleucel (Yescarta)

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
CPT codes covered if selection criteria are met:
38204 - 38205, 38207 - 38230	Bone marrow or stem cell services/procedures (except autologous)
38242	Allogeneic lymphocyte infusions [not covered for allogenic CAR donor lymphocyte infusion]
CPT codes not covered for indications listed in the CPB:
Pre-transplant infusion of donor lymphocytes treated with extracorporeal photochemotherapy-no specific codes
Other CPT codes related to the CPB:
36511	Therapeutic apheresis; for white blood cells
86812 - 86822	Compatibility studies code range
HCPCS codes covered if selection criteria are met:
S2150	Bone marrow or blood-derived stem-cells (peripheral or umbilical), allogeneic or autologous, harvesting, transplantation, and related complications; including: pheresis and cell preparation/storage; marrow ablative therapy; drugs, supplies, hospitalization with outpatient follow-up; medical/surgical, diagnostic, emergency, and rehabilitative services; and the number of days of pre- and post-transplant care in the global definition
HCPCS codes not covered for indications listed in the CPB:
J1442	Injection, filgrastim (G-CSF), excludes biosimilars, 1 microgram
J1447	Injection, tbo-filgrastim, 1 microgram
J2505	Injection, pegfilgrastim, 6 mg
Q5101	Injection, filgrastim (G-CSF), biosimilar, 1 microgram (Zarxio)
Q5108	Injection, pegfilgrastim-jmdb, biosimilar, (fulphila), 0.5 mg
Q5110	Injection, Pegfilgrastim-cbqv, biosimilar, (udenyca), 0.5 mg
Q5120	Injection, pegfilgrastim-bmez, biosimilar, (ziextenzo), 0.5 mg
Q5122	Injection, pegfilgrastim-apgf, biosimilar, (nyvepria), 0.5 mg
ICD-10 codes covered if selection criteria are met:
C91.00 - C91.02	Acute lymphoblastic leukemia [ALL]
C92.00 - C92.02	Acute myeloblastic leukemia
C92.10 - C92.12	Chronic myeloid leukemia, BCR/ABL-positive
Z94.81	Bone marrow transplant status
Z94.84	Stem cells transplant status
ICD-10 codes not covered for indications listed in the CPB:
C90.00 - C90.02	Multiple myeloma
C43.0 - C43.9	Malignant melanoma of skin
T86.11	Kidney transplant rejection
T86.21	Heart transplant rejection
T86.31	Heart-lung transplant rejection
T86.41	Liver transplant rejection
T86.5	Complications of stem cell transplant
T86.810	Lung transplant rejection
T86.890	Other transplanted tissue rejection
Z76.82	Awaiting organ transplant status code [pre-transplant infusion of donor lymphocytes treated with extracorporeal photochemotherapy]
Z94.0 - Z94.9	Transplanted organ and tissue status [prevention of graft rejection]

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Background

High-dose chemotherapy (HDC) in combination with allogeneic bone marrow transplantation results in remission in significant numbers of patients with chronic myelogenous leukemia (CML), acute myeloid leukemia (AML) or acute lymphocytic leukemia (ALL).  However, disease relapse is a major cause of treatment failure, and salvage treatment options for these patients are limited.  Patients can either be treated with an additional course of conventional chemotherapy or a second round of HDC and repeat allogeneic transplantation.  Conventional chemotherapy is unlikely to result in a complete durable remission, and the morbidity and mortality of a second allogeneic transplant is unacceptably high.  Furthermore, patients with CML have been treated with interferon.  While this treatment can be associated with normalization of peripheral blood counts, interferon fails to eradicate the malignant clone of cells.

Donor lymphocyte infusion (DLI), also known as donor leukocyte or buffy coat infusion, has been used in an attempt to stimulate a donor-versus-leukemia (GVL) reaction and thus eradicate the malignant clone of cells.  Donor lymphocyte infusion entails the collection (from the original donor) of peripheral lymphocytes during an apheresis procedure; donors generally undergo 2 to 8 procedures.  The lymphocytes are then simply infused into the patient either immediately or after frozen storage.  Donor lymphocyte infusion differs from allogeneic bone marrow transplantation in that it is not preceded by chemotherapy and T cells are not depleted.  Lymphocyte infusion with a defined T-cell dose can cause a profound GVL effect and is an effective form of salvage immunotherapy in allogeneic marrow transplanted recipients.  The advantage in using DLI versus second allogeneic transplantation is the lower treatment-related morbidity and mortality.

The GVL effect is a well-described phenomenon, which is associated with the presence of graft-versus-host disease (GVHD).  For example, the likelihood of relapse post-allogeneic transplantation is lower in those patients who experience either acute or chronic GVHD.  In addition, there is a higher rate of relapse in patients receiving a syngeneic (identical twin) transplant compared to allogeneic transplant.  However, the presence of GVL is not dependent on the presence of GVHD.  For example, the rate of leukemic relapse is higher in patients receiving T- cell depleted allogeneic marrow, even after controlling for the degree of GVHD.  This observation suggests that there may be a distinct subset of T cells responsible for GVL.  Donor lymphocyte infusion attempts to harness the anti-leukemic properties of donor T cells.

In a recent review on adoptive allogeneic cellular therapy, Peggs and Mackinnon (2001) stated that DLI is effective in generating anti-tumor responses, especially for relapsed chronic-phase CML.  Response rates and durability appear lower with myeloma, AML and myelodysplasia syndrome, and minimal with ALL.  There is relatively little data on indolent lymphoid malignancies.  This is in agreement with the observation of Slavin and associates (2001) who reported that pre-clinical and clinical studies have indicated that much more effective eradication of the host immunohematopoietic system cells can be attained by adoptive allogeneic cellular therapy with DLI following bone marrow transplantation.  Thus, eradication of blood cancer cells, particularly in patients with CML and, less frequently, in patients with other hematological malignancies, can frequently be achieved despite the complete resistance of such tumor cells to maximally tolerated doses of chemo- and radio-therapy.

In a review on DLI for the treatment of hematologic malignancies in relapse following allogeneic blood or marrow transplantation, Luznik and Fuchs (2002) reported that DLI induces complete remissions in the majority of patients with CML in early-stage relapse and in less than 30 % of patients with relapsed acute leukemia, myelodysplasia, and multiple myeloma.  Remissions of chronic-phase CML induced by DLI are durable, but as many as half of patients with other diseases ultimately relapse.

Pre-planned DLI has also been used as part of transplant protocols in persons with hematologic malignant diseases who have not relapsed.  Donor lymphocyte infusion is intended to facilitate establishment of full donor chimerism (complete donor stem cell grafting in the recipient's bone marrow) and potentiation of anti-tumor effect (graft-versus-tumor reaction) (Cheong et al, 2002).

There is also ongoing research on the genetic modification of donor lymphocytes.  Transplantation of suicide gene modified allogeneic T lymphocytes is an approach to prevent T-cell mediated GVHD while preserving the GVL effect of an allograft.  However, existing techniques allow insufficient transduction of T lymphocytes.  Further investigation is needed to develop more efficient gene transfer protocols and is possible value in the treatment of hematological malignancies.

Beitinjaneh et al (2012) stated that the role of DLI in mediating the graft-versus-myeloma (GVM) effect after allogeneic hematopoietic stem cell transplant (allo-HCT) is not clearly defined.  These investigators evaluated the safety and utility of DLI in patients with either persistent or recurrent multiple myeloma (MM) after allo-HCT.  A total of 23 patients with MM received DLI after allo-HCT between July 1996 and June 2008 were included in this study.  Eight patients received preemptive DLI for residual disease (RD) while 15 patients received DLI for the treatment of recurrent or progressive disease (PD).  These researchers evaluated the response to DLI and the factors that may predict a response.  Median DLI dose was 3.3 × 10(7) CD3 + cells (range of 0.5 to 14.8 × 10(7)).  Grade II to IV acute GVHD was seen in 5 patients (22 %).  Median follow-up in surviving patients was 24 months.  Five of 23 patients (22 %) achieved a complete or a very good partial response (2 CR, 3 VGPR), while 8 patients (34 %) had stable disease (SD) after the DLI.  Patients who received DLI for RD had a higher response rate (greater than or equal to VGPR 50 % versus 7 %, p = 0.03), a longer overall survival (28.3 versus 7.6 months, p = 0.03) and a trend toward longer progression-free survival (11.9 versus 5.2 months, p = 0.1).  In this largest single institution study, the authors concluded that the use of preemptive, non-manipulated DLI for RD after reduced-intensity conditioning allo-HCT is encouraging, and it was associated with a higher response rate and a longer overall survival when given preemptively.  They stated that the role of DLI needs to be further explored in prospective clinical trials.

According to the 2009 edition of Thomas’ Hematopoietic Cell Transplantation, in patients with poor graft function  following allogeneic transplantation, CD34+ selected cell boost following granulocyte-colony stimulating factor (G-CSF) mobilization was associated with a high likelihood of hematopoietic cell recovery and a low risk of GVHD. Patients did not receive conditioning prior to the CD34+ cell boost. It is unclear how long to wait before requesting a second donation of cells.

An UpToDate review on “Immunotherapy for the prevention and treatment of relapse following hematopoietic cell transplantation” (Negrin, 2014) states that “Various techniques have been used to manipulate the donor lymphocyte graft in an effort to increase the lymphocyte specificity to eradicate tumor while minimizing effects on the host.  As yet, these techniques are considered experimental and require further study in humans before they can be widely applied”.

Intrathecal Donor Lymphocyte Infusion

Yanagisawa et al (2016) reported on the case of an 8-year old boy with a bone marrow relapse of T cell acute lymphoblastic leukemia underwent stem-cell transplantation from a human leukocyte antigen (HLA)-haploidentical mother. Five months later, he relapsed with central nervous system (CNS) involvement.  Systemic chemotherapy and repeated intrathecal chemotherapy induced consciousness disturbances and frequent arrhythmia, prompting discontinuation of the chemotherapy.  He had already received an 18-Gy prophylactic cranial irradiation, an 8-Gy total body irradiation, and a 15-Gy local irradiation for pituitary gland involvement.  Thus, these researchers performed 5 intrathecal DLIs (IDLIs) in escalating doses from 1 × 10(4) up to 1 × 10(6) cells/kg.  All IDLIs were safe without infusion reactions or GVHD.  After the 2nd and later IDLIs, donor mononuclear cells were continuously detected in cerebrospinal fluid; however, he did not achieve donor-dominant chimerism.  The authors concluded that based on this case and 4 cases reported in the literature, the effectiveness of IDLI therapy is limited for CNS relapse of hematological malignancies.  However, they suggested that IDLI remains a feasible and safe option, as no GVHD or other adverse effects occurred, even in the HLA-haploidentical setting.  These investigators noted that they will make further efforts to increase the efficacy.

Zhao and colleagues (2019) noted that allo-HSCT is an effective measure for the treatment of hematological disease.  With the progress and widespread use of allo-allogeneic hematopoietic stem cell transplantation (allo-HSCT), Epstein-Barr virus (EBV)-related CNS diseases have gotten more and more attention because of its poor prognosis and OS.  Since currently there is no standard treatment for patients with EBV-associated CNS diseases and reported therapies are heterogeneous with mixed results, these investigators attempted to develop a novel therapeutic method.  They applied a regimen of IDLI in 3 patients with EBV-associated CNS diseases following allo-HSCT in addition to immunosuppressants reduction and combined anti-viral therapy.  All 3 patients were responsive to this therapy: all clinical symptoms and EBV load in CSF were resolved 10, 17, and 12 days following initial IDLI, respectively, and magnetic resonance imaging (MRI) showed that lesions of case 1 and 2 disappeared 15 and 19 days following initial IDLI, respectively.  Even more appealing, there were no acute or chronic adverse reactions during the infusion and up to 23 months of follow-up.  The authors concluded that IDLI appeared to be a safe and effective method for EBV-associated CNS diseases in allo-HSCT recipients; these researchers recommended this approach for further investigation.

Multiple Myeloma

Oostvogels and colleagues (2017) stated that DLI can induce durable remissions in MM patients, but this occurs rather infrequently.  As the graft-versus-tumor (GvT) effect of DLI depends on the presence of host-dendritic cells (DCs), these researchers tested in a phase I/II clinical trial whether the effectiveness of DLI could be improved by simultaneous vaccination with host-DCs.  They also analyzed the possibility of further improving the GvT effect by loading the DCs with peptides of mis-matched hematopoietic cell-specific minor histocompatibility antigens (mHags).  A total of 15 MM patients not responding to a 1st DLI were included in this study; 11 patients could be treated with a 2nd equivalent dose DLI combined with DC vaccinations, generated from host monocytes (moDC).  For 4 patients, the DC products did not meet the quality criteria.  In 4 of the treated patients the DCs were loaded with host mHag peptides.  Toxicity was limited and no acute GVHD occurred.  Most patients developed objective anti-host T-cell responses and in 1 patient a distinct mHag-specific T-cell response accompanied a temporary clinical response.  The authors concluded that these findings confirmed that DLI combined with host-DC vaccination, either unloaded or loaded with mHag peptides, is feasible, safe and capable of inducing host-specific T-cell responses.  They stated that the limited clinical effects may be improved by developing more immunogenic DC products or by combining this therapy with immune potentiating modalities like checkpoint inhibitors.

National Comprehensive Cancer Network’s clinical practice guideline on “Multiple myeloma” (Version 3.2017) states that “Patients whose disease either does not respond to or relapse after allogeneic stem cell grafting may receive donor lymphocyte infusions to stimulate a beneficial graft-versus-myeloma effect or other myeloma therapies on or off a clinical trial”.  There is no explicit recommendation regarding the use of DLI.

Furthermore, an UpToDate review on “Treatment of relapsed or refractory multiple myeloma” (Rajkumar, 2017) does not mention DLI as a management tool.

Groger and colleagues (2018) noted that the major reason for treatment failure after allografting in MM is relapse; DLIs are considered a valuable post-transplant strategy mainly for relapsed patients but using them to prevent relapse in MM has been rarely reported.  These researchers examined the efficacy of prophylactic DLIs after allo-HSCT in MM patients with a long-term follow-up of more than 5 years.  A total of 61 patients with MM who did not relapse or develop disease progression after allo-HSCT were treated with prophylactic DLI in an escalating fashion (overall 132 DLI procedures) to deepen remission status and prevent relapse.  Overall response rate (ORR) to DLI was 77 %; 33 patients (54 %) up-graded their remission status, 41 patients (67 %) achieved or maintained complete remission, and 26 % achieved a molecular remission.  Incidence of acute GVHD grade II to IV was 33 % and no DLI-related mortality was noted.  After a median follow-up of 68.7 months from 1st DLI the estimated 8-year progression-free survival (PFS), and overall survival (OS) in a landmark analysis was 43 % (95 % confidence interval [CI]: 28 % to 57 %) and 67 % (95 % CI: 53 % to 82 %), respectively, with best outcome for patients who acquired molecular remission (8-year PFS was 62 % and 8-year OS was 83 %).  The authors concluded that prophylactic escalating DLI in a selected cohort of MM patients to prevent relapse after allograft resulted in a low incidence of severe GVHD and encouraging long-term results, especially if molecular remission is achieved.

Chimeric Antigen Receptor-Modified Donor Lymphocyte Infusion

Wang and colleagues (2019) noted that the value of chimeric antigen receptor-modified DLI (CAR-DLI) is unclear in B-cell acute lymphoblastic leukemia (B-ALL), particularly in patients with relapsed diseases following allo-HSCT.  In this study, a total of 5 B-ALL patients who relapsed following allo-HSCT received CAR-DLI (CAR-DLI group), and the outcome was compared with 27 relapsed B-ALL patients who received DLI therapy (DLI group).  The median complete remission duration of CAR-DLI group was significantly (p = 0.020) longer when compared with DLI group: 9 months (range of 2 to 29) versus 3.2 months (range of 0 to 17.4).  Furthermore, patients receiving CAR-DLI showed significant (p = 0.049) survival advantage over DLI group, with median OS of 12 months (range of 3 to 29) and 3.7 months (range of 0 to 65), respectively.  Of note, no patient developed acute GVHD in the CAR-DLI group, while incidence of acute GVHD grades I to II and grades III to IV were 2 (7 %) and 4 (14.8 %) in the DLI group, respectively.  In addition, cytokine release syndrome in CAR-DLI group was manageable.  The authors concluded that the findings of this study demonstrated that CAR-DLI significantly improved the survival of B-ALL patients relapsed following allo-HSCT, thus indicating that CAR-DLI may represent an alternative and more effective therapy for B-ALL patients with relapsed diseases.  This was a small study (n = 5 for the CAR-DLI group); its findings need to be validated by well-designed studies.

Concomitant Use of Blinatumomab and Donor Lymphocyte Infusion for Mixed-Phenotype Acute Leukemia

Durer and colleagues (2019) stated that blinatumomab and DLI combination is a promising cancer therapy, whereby blinatumomab might achieve an initial reduction in leukemic-cell burden using T cells, and after tumor clearance, DLI can potentially stimulate the donor immune system to achieve longer lasting remission.  These researchers presented the case of a 51-year old woman with mixed phenotype acute leukemia who had a hematologic relapse 3 months after she received total body irradiation (TBI)-based myeloablative allo-HSCT from an unrelated HLA-matched (10/10) donor and achieved complete remission with minimal residual disease (MRD) negativity by multi-parameter flow cytometry using the combination of blinatumomab and DLI.  The authors concluded that to the best of their knowledge, this was the 1st report to describe the use of blinatumomab and DLI combination therapy in the treatment of B/myeloid mixed phenotype acute leukemia.  These preliminary findings from a single-case study need to be validated by well-designed studies.

Donor Lymphocyte-Derived Natural Killer Cells for the Treatment of Melanoma

Dang and colleagues (2020) stated that natural killer (NK) cells provide a natural defense against MHC-I-negative tumors, such as melanoma.  Donor lymphocyte infusion (DLI) containing NK cells, a form of adoptive immunotherapy used after allogenic bone marrow transplantation (allo-BMT), promotes anti-tumor immune responses but is often associated with life-threatening complications such as GVHD.  These researchers showed that without prior allo-BMT, DLI provoked melanoma control associated with the infiltration and persistence of the transferred NK cells.  This allograft acceptance did not correlate with an increase of GVHD; instead it correlated with the expansion and activation of tumor-infiltrating NK cells that expressed the cytotoxic molecules (e.g., IFNγ and granzyme B) and maturation signatures (e.g., CD11bhiCD27lo and KLRGhi/CD43hi).  The development of beneficial tumor-infiltrating NK cells of DLI origin required host CD4+ T-cell help in part by producing interleukin-2 (IL-2), as well as by limiting regulatory CD4+ T cells (Treg).  IL-2 blockade impaired the NK-dependent melanoma control, which could not be rescued by IL-2 administration beyond CD4+ T-cell help.  The authors stated that these findings linked NK allograft acceptance-CD4+ T-cell help cross-talk to melanoma development without the need of allo-BMT.  These researchers thereby helped define that tumor-infiltrating NK cells of DLI origin may serve as effective therapeutic targets for controlling melanoma.

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on “Cutaneous melanoma” (Version 3.2020) does not mention DLI containing NK cells as a therapeutic option.

Prophylactic Donor Lymphocyte Infusion for Relapse Prevention

Kothari and co-workers (2020) stated that prophylactic donor lymphocyte infusion (pDLI) is a potential intervention to prolong remission for patients receiving allogeneic hematopoietic stem cell transplantation (allo-SCT), however, the optimal timing and dose are unknown.  These researchers carried out a prospective trial examining the feasibility of early withdrawal of immunosuppression (WOI) at day 60 followed by dose escalation of pDLI after alemtuzumab-based, T-cell depleted conditioning for patients with high-risk hematologic malignancies.  pDLI were administered at day 75 to day 90 and again in 4 to 8 week intervals with receipt of up to 5 pDLI infusions.  A total of 46 patients with matched-related donors (MRD) and 29 patients with matched-unrelated donors (MUD) were considered; 28 MRD patients were able to undergo WOI, 26 patients (93 %) received at least 1 DLI, 16 patients (57 %) received 3+, and 7 patients (25 %) received 5 pDLI.  Only 7 MUD patients were able to undergo WOI, 4 (57 %) received at least 1 pDLI, 1 patient (14 %) received 3 DLI, and no patients received all 5.  Median PFS for patients on the study was 366 days.  The estimated 2-year PFS and OS rates for all patients were 41 % (95 % CI: 32 to 54 %) and 51 % (95 % CI: 41 to 63 %) compared with 57 % (95 % CI: 41 to 77 %) and 67 % (95 % CI: 52 to 86 %) for patients who received at least 1 pDLI.  Furthermore, MRD patients receiving pDLI had faster immune re-constitution and improved donor chimerism. The authors proposed a novel dosage and treatment schedule for pDLI that is tolerable for patients who have received MRD allo-SCT and would lead to improved outcomes.

Poonsombudlert and colleagues (2020) noted that primary disease relapse (PDR) of malignant hematologic conditions following standard HSCT is one of the most challenging diseases; thus, ongoing investigations are aiming at relapse prevention and minimizing the transplant-related side effects.  Prophylactic donor lymphocytes had been proposed as a valuable strategy for PDR prevention, but early studies had been discouraging due to the limited benefit and possible association with acute GVHD (aGVHD).  Therefore, these researchers conducted a meta-analysis to examine the association between pDLI use, PDR, aGVHD and OS.  They carried out a comprehensive literature search in Medline, Cochrane library and Embase data-base from inception to May 2019 for studies that assessed the association between pDLI and PDR.  These investigators conducted a random effect meta-analysis of 9 studies entailing a total of 748 subjects (pDLI = 398, non-pDLI = 350) and reported the pooled odd ratio (OR) for association of pDLI use, PDR, aGVHD and OS.  They found a significant decreased odd of PDR in the pDLI group (pooled OR = 0.42, 95 % CI: 0.30 to 0.58, I2 = 0 %), however, there was no significant increased odd of aGVHD (pooled OR of 0.98, 95 % CI: 0.56 to 1.72, I2 = 0.8 %).  These researchers also found that there was an increased odd of OS (pooled OR 3.17, 95 % CI: 1.85 to 5.45, I2 = 50.2 %).  The authors found that there were significantly decreased odd of PDR and increased odd of OS in the pDLI group compared to the control group, however, there was no statistically significant increased odd of aGVHD as suggested by previous studies.  These researchers concluded that pDLI is a potentially valuable method for post-transplant PDR prevention.

The authors stated that this study had several drawbacks.  First, the 9 eligible studies that these investigators included were all conducted in adult patients with advance high-risk malignant hematologic diseases; thus, this could limit the external validity of this meta-analysis to patients in other groups.  Second, as these researchers included patients with various indications for transplant, diverse pre-transplant co-morbidities as well as various disease statuses, these differences likely accounted for the heterogeneity of the outcomes, but they were able to identify pDLI manipulation strategy, pDLI administration time and pDLI CD3+ cell dose as the sources of heterogeneity.  Moreover, these researchers also noted that there might be selection bias in the recruitment process of some studies as most patients with history of GVHD were often excluded from the treatment group.

Schmidt and associates (2020) stated that treatment for relapse of CML following HCT includes tyrosine kinase inhibitors (TKIs) with or without DLIs, but the most effective treatment strategy is unknown.  This study was carried out via the Center for International Blood and Marrow Transplant Research (CIBMTR) data-base.  These investigators retrospectively reviewed all patients reported to the CIBMTR registry from 2002 to 2014 who underwent HCT for CML and were alive 30 days post-relapse.  A total of 215 HCT recipients relapsed and were analyzed in the following groups: TKI alone (n = 128); TKI with DLI (n = 48); and DLI without TKI (n = 39).  In multi-variate analysis, disease status prior to HCT had a significant effect on OS.  Patients who received a DLI alone compared with a TKI with a DLI had inferior survival (hazard ratio [HR], 2.28; 95 % CI: 1.23 to 4.24; p = 0.009).  Those who received a TKI alone had similar survival compared with those who received a TKI with a DLI (p = 0.81).  The authors concluded that these findings supported that despite use of TKIs pre-transplantation, TKI salvage therapy continued to provide significant survival following relapse in patients with CML following HCT.  Moreover, these data did not suggest that adding a DLI to a TKI provided an improvement in OS.

Tsirigotis and associates (2021) stated that patients with high-risk acute leukemia have a high risk of relapse after allo-SCT.  In an effort to reduce the relapse rate, various therapeutic methods have been implemented into clinical practice.  Among them, pDLI has shown significant efficacy.  However, the widespread application of pDLI has been restricted mostly due to concerns regarding the development of GVHD.  These researchers examined the safety and efficacy of a novel method of pDLI based by repetitive administration of low lymphocyte doses.  DLI was administered to patients with high-risk acute leukemia at a dose of 2 × 106/kg CD3-positive cells.  DLI at the same dose was repeated every 2 months for at least 36 months post-allo-SCT, or until relapse or any clinical or laboratory feature suggested GVHD, whichever occurred first.  A total of 44 patients with a median age of 53 years (range of 20 to 67) who underwent allo-SCT between 2011 and 2020 were included in this trial; 33 patients with high-risk AML and 11 with high-risk ALL following allo-SCT from a matched sibling (MSD, n = 38) or a matched-unrelated donor (MUD, n = 6) received pDLI; 23 patients were in CR1, all with unfavorable genetic features; 12 patients were in CR2 or beyond; and 9 patients had refractory disease at the time of transplant; 10 out of 23 patients in CR1 had detectable MRD at the time of allo-SCT.  Disease risk index (DRI) was high and intermediate in 21 and 23 patients, respectively.  Conditioning was myeloablative (MAC) in 36 and reduced intensity (RIC) in 8 patients, while GVHD prophylaxis consisted of cyclosporine-A in combination with low-dose alemtuzumab in 39 patients or with low-dose MTX in 5 patients, respectively.  A total of 35 patients completed the scheduled treatment and received a median of 8 DLI doses (range of 1 to 35); 15 out of 35 patients received all planned doses, while DLI was discontinued in 20 patients.  Reasons for discontinuation included GVHD development in 9, donor unavailability in 7, disease relapse in 3, and secondary malignancy in 1 patient, respectively; 9 patients were still on treatment with DLI, and they received a median of 4 (range of 2 to 12) doses; 14 % of patients developed transient grade-II acute GVHD while 12 % developed chronic GVHD (cGVHD) post-DLI administration.  Acute GVHD was managed successfully with short course steroids, and 4 out of 5 patients with cGVHD were disease-free and off immunosuppression.  With a median follow-up of 44 months (range of 8 to 120), relapse-free (RFS) and OS were 74 %, (95 % CI: 54 to 87 %) and 78 %, (95 % CI: 58 to 89 %) respectively, while the cumulative incidence of non-relapse mortality (NRM) was 13 % (95 % CI: 4 to 28 %).  The cumulative incidence of relapse in patients with intermediate and high DRI was 7 % and 15 %, respectively.  The authors concluded that prolonged (up to 3 years) low-dose pDLI administered every 2 months was safe and effective in reducing relapse rate in patients with high-risk acute leukemia.  The low-dose repetitive administration DLI strategy reduced the risk of DLI-mediated GVHD, while the prolonged repeated administration helped in preventing relapse, possibly by inducing a sustained and prolonged immunological pressure on residual leukemic cells.  These researchers stated that this novel strategy deserves further testing in larger cohort of patients with high-risk acute leukemia.  Moreover, these researchers stated that one of the study limitations was the rather small number of patients, which did not allow for meaningful comparisons between subgroups of patients with different disease characteristics.

Su and coworkers (2021) noted that pDLI could reduce relapse in patients with refractory/relapsed acute leukemia (RRAL) undergoing allo-HSCT; however, optimal timing of pDLI remains uncertain.  These researchers compared the outcomes of 2 strategies for pDLI based on time from transplant and MRD status in patients with RRAL.  For patients without grade II to IV aGVHD on day +60, pDLI was given on day +60 regardless of MRD in cohort 1; and was given on day +90 unless MRD was positive on day +60 in cohort 2.  A total of 161 patients with RRAL were enrolled, including 83 in cohort 1 and 78 in cohort 2.  The extensive cGVHD incidence in cohort 2 was lower than that in cohort 1 (10.3 % versus 27.9 %, p = 0.006) and GVHD-free/relapse-free survival (GRFS) in cohort 2 was superior to that in cohort 1 (55.1 % versus 41.0 %, p = 0.042).  The 2-year relapse rate, OS and leukemia-free survival were comparable between the 2 cohorts (29.0 % versus 28.2 %, p = 0.986; 63.9 % versus 64.1 %, p = 0.863; 57.8 % versus 61.5 %, p = 0.666).  The authors concluded that delaying pDLI to day +90 based on MRD for patients with RRAL undergoing allo-HSCT could lower extensive cGVHD incidence and improve GRFS without increasing incidence of leukemia relapse compared with pDLI on day +60.  These researchers stated that the findings of this study provided evidence for examining optimal timing of pDLI in patients with RRAL undergoing allo-HSCT.

The authors stated that this study had several drawbacks.  Although this study was based on 2 prospective cohorts, they were non-parallel, which could not exclude the influence of factors such as improvement in medical technology and supportive treatment.  Furthermore, no randomized studies have shown that pDLI is superior to non-pDLI.  They stated that large-scale RCTs are needed to validate outcomes of patients undergoing non-pDLI and different pDLI strategies.

Zhang et al (2021) stated that relapse is the main cause of treatment failure for leukemia patients with unfavorable gene mutations who receive allo-HSCT.  Currently, there is no consensus on the indication of DLI for prophylaxis of relapse following allo-HSCT.  In a prospective, single-arm, pilot study, these researchers examined the tolerance and efficacy of pDLI in patients with unfavorable gene mutations such as FLT3-ITD, TP53, ASXL1, DNMT3A or TET2.  Prophylactic use of decitabine followed by DLI was planned in patients with TP53 or epigenetic modifier gene mutations.  The prophylaxis was planned in 46 recipients: it was administered in 28 patients and it was not administered in 18 patients due to contraindications.  No DLI-associated pancytopenia was observed.  The cumulative incidences of grade II to IV and III to IV aGVHD at 100 days post-DLI were 25.8 % and 11.0 %, respectively.  The rates of GVHD, non-relapse mortality and relapse at 3 years post-DLI were 21.6 %, 25.0 % and 26.1 %, respectively.  The 3-year RFS and OS rates were 48.9 % and 48.2 %, respectively.  Acute GVHD (HR: 2.30, p = 0.016) and relapse (HR: 2.46, p = 0.003) after DLI were independently associated with inferior OS.  The authors concluded that these findings showed the feasibility of pDLI with/without decitabine in the early stage after allo-HSCT in patients with unfavorable gene mutations.

The authors stated that the major drawbacks of this study were the limited numbers of patients, and the lack of a control group.  Even though all patients with unfavorable gene mutations were scheduled to receive the prophylactic strategy, not all of the patients had the opportunity to receive pDLI because of early relapse, or persistent GVHD,  Nevertheless, the patients enrolled in this study were consecutive with a consistent protocol for pDLI, which guaranteed the objectivity of the conclusion.  Furthermore, the data of 12 patients who were treated contemporaneously under the same protocol but did not receive DLI due to various contraindications were also shown in Supporting Information.  To some extent, these data may provide a reference for GVHD, NRM and other transplantation toxicities.  The results of this study provided the following insights.  First, the strategy to prevent early relapse following transplantation should be intensified prior to transplantation.  Second, persistent GVHD and poor hematopoietic reconstitution might not be contraindications for prophylactic D + DLI.

Pre-Transplant Infusion of Donor Lymphocytes Treated with Extracorporeal Photochemotherapy

Schneiderman et al (2022) noted that recipients of solid organ transplantation (SOT) rely on life-long immunosuppression (IS), which is associated with significant side effects.  Extracorporeal photochemotherapy (ECP) is a safe, existing cellular therapy used to treat transplant rejection by modulating the recipient's own blood cells.  These researchers sought to induce donor-specific hypo-responsiveness of SOT recipients by infusing ECP-treated donor leukocytes before transplantation.  They used major histocompatibility complex mismatched rodent models of allogeneic cardiac, liver, and kidney transplantation to test this novel strategy.  Leukocytes isolated from donor-matched spleens for ECP treatment (ECP-DL) were infused into transplant recipients 7 days before SOT.  Pre-transplant infusion of ECP-DL without additional IS was associated with prolonged graft survival in all models.  This innovative approach promoted the production of tolerogenic dendritic cells and regulatory T-cells with subsequent inhibition of T-cell priming and differentiation, along with a significant reduction of donor-specific T-cells in the spleen and grafts of treated animals.  The authors concluded that this new application of donor-type ECP-treated leukocytes provided insight into the mechanisms behind ECP-induced immunoregulation and holds promise in the prevention of graft rejection and reduction in need of global immune suppressive therapy in patients following SOT.

These researchers stated that several questions remain regarding optimization of this approach, providing rich potential for future research in the field.  First, the concern regarding the potential of ECP-DL infusion to create sensitization that may promote antibody-mediated rejection (AMR).  Patients undergoing ECP therapy for lung transplant demonstrated a reduction of donor specific antibodies (DSA) production over time.  In these researchers’ hands, ECP-DL did not cause acute sensitization, rather, it significantly inhibited de-novo DSA (dnDSA) production, likely due to its immunomodulatory effect on T-cells.  dnDSA levels did rise over time without additional IS therapy but was significantly lower in the ECP-DL group.  Further investigations are needed to examine if dnDSA is responsible for late rejection and whether addition of post-transplant standard ECP or low-dose IS therapy will prevent dnDSA production over time.  A 2nd question entails the evaluation of immune response kinetics, and timing of cell infusions.  Precedent exists for cryo-preserving autologous mononuclear cells with subsequent thawing and ECP-treatment; thus, there can be opportunities to give subsequent doses of ECP-DL following transplant.  Their data in rats receiving ECP-treated host cells post-liver transplant supports the approach of standard ECP following SOT and can be compared to re-treatment with donor cells.  Next, these investigators demonstrated that ECP-treated cells were processed primarily in the spleen, raising the question of whether the spleen is needed for these interactions to occur.  Finally, further investigation examining infusion time-points closer to the day of transplant could allow for a version of this protocol to be employed in the setting of deceased donor transplantation, especially given the capacity to maintain grafts for 24 hours following procurement.  In summary, we believe the treatment of donor cells with ECP prior to SOT has significant promise to induce hypo-responsiveness of the recipient’s immune system, allowing judicious use and taper of IS. Thereafter, standard ECP treatment of recipient cells could serve to prolong the effect, potentially indefinitely.

Granulocyte Colony-Stimulating Factor (GCSF)-Stimulated Donor Lymphocyte Infusions for Relapsed Disease Following Allogeneic Hematopoietic Cell Transplantation

Kirkham et al (2022) noted that DLI can produce graft-versus tumor effects to treat relapse after allo-HCT, however, durable responses remain uncommon.  In a systematic review and meta-analysis, these investigators examined if DLI collected after stimulation with granulocyte colony-stimulating factor (GCSF; G-DLI) could improve clinical outcomes.  A total of 16 studies (4 controlled) entailing 585 patients were identified in a systematic search up to September 17, 2020.  A meta-analysis revealed no significant difference in the risk of all-cause mortality (RR: 0.94, 95 % CI: 0.52 to 1.68, p = 0.82; n = 3 studies) or relapse-related mortality (RR: 0.72, 0.44 to 1.18, p = 0.19; n = 3 studies) between G-DLI and conventional DLI (C-DLI) groups.  G-DLI products had similar mean CD3+ cells compared to C-DLI products; however, median CD34+ cells/kg were increased.  No improvement in disease progression, complete response (CR) rates, or risk of developing GVHD was observed with G-DLI; however, greater non-relapse mortality was observed compared to C-DLI.  The authors concluded that alternative approaches to enhancing graft-versus-tumor effects are needed.

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References